Comparative Genomics of the Major Histocompatibility Complex (MHC) of Felids

Abstract

This review summarizes the current knowledge on the major histocompatibility complex (MHC) of the family Felidae. This family comprises an important domestic species, the cat, as well as a variety of free-living felids, including several endangered species. As such, the Felidae have the potential to be an informative model for studying different aspects of the biological functions of MHC genes, such as their role in disease mechanisms and adaptation to different environments, as well as the importance of genetic diversity for conservation issues in free-ranging or captive populations. Despite this potential, the current knowledge on the MHC in the family as a whole is fragmentary and based mostly on studies of the domestic cat and selected species of big cats. The overall structure of the domestic cat MHC is similar to other mammalian MHCs following the general scheme "centromere-MHC class I-MHC class III-MHC class II" with some differences in the gene contents. An unambiguously defined orthologue of the non-classical class I HLA-E gene has not been identified so far and the class II DQ and DP genes are missing or pseudogenized, respectively. A comparison with available genomes of other felids showed a generally high level of structural and sequence conservation of the MHC region. Very little and fragmentary information on in vitro and/or in vivo biological functions of felid MHC genes is available. So far, no association studies have indicated effects of MHC genetic diversity on a particular disease. No information is available on the role of MHC class I molecules in interactions with Natural Killer (NK) cell receptors or on the putative evolutionary interactions (co-evolution) of the underlying genes. A comparison of complex genomic regions encoding NK cell receptors (the Leukocyte Receptor Complex, LRC and the Natural Killer Cell Complex, NKC) in the available felid genomes showed a higher variability in the NKC compared to the LRC and the MHC regions. Studies of the genetic diversity of domestic cat populations and/or specific breeds have focused mainly on DRB genes. Not surprisingly, higher levels of MHC diversity were observed in stray cats compared to pure breeds, as evaluated by DRB sequencing as well as by MHC-linked microsatellite typing. Immunogenetic analysis in wild felids has only been performed on MHC class I and II loci in tigers, Namibian leopards and cheetahs. This information is important as part of current conservation tasks to assess the adaptive potential of endangered wild species at the human-wildlife interface, which will be essential for preserving biodiversity in a functional ecosystem.

Keywords: Felis catus; comparative genomics; conservation genetics; domestic cat; felidae; genetic diversity; major histocompatibility complex; natural killer cell receptor ligands.

FIGURE 1

Schematic comparison of the Felis catus MHC region located on chromosome B2 (based on the sequence EU153401.1 by Yuhki et al., 2008) and compared with the human (HLA) and canine (DLA) MHC regions. Filled triangles represent potentially functional genes; unfilled triangles represent pseudogenes (based on Okano et al., 2020). DLA class I is presented as rectangles, since the original material does not provide gene orientation and original data is not available (Yuhki et al., 2007). The DLA class II map is based on Debenham et al., 2005, for HLA, it is based on the human genome GRCh38.p13.

FIGURE 2

Organization of Natural Killer Complex genomic region in Canada lynx (Lynx canadensis) on chromosome B4 in comparison with the human and canine NKCs. Presumably functional genes (solid color triangles) along with pseudogenes/gene fragments (open triangles) are grouped in two families, KLRC (blue) and KLRH (yellow). The lower panel shows possible protein products, which may form functional cell receptors by homo- or heterodimerization. Their predicted signaling in terms of activation (+) or inhibition (−) is based on the presence of positively charged amino acid (H—histidine, K—lysine, R—arginine) in the transmembrane region or the immunoreceptor tyrosine-based inhibitory motifs (red rectangles) in cytoplasmic tail, respectively. When both features are present, the resulting signal is uncertain. Based on similarities to other mammalian species, all these putative proteins, except the products of the KLRK and KLRJ genes, could bind MHC class I ligands. The KLRK product can bind the stress-induced-self ligands MIC and ULBP; the ligands of KLRJ remain unknown. The organization of the canine Natural Killer Complex is based on the genome GCA_014441545.1, while the human NKC organization is based on Schwartz et al. (2017).